Antiplatelet therapy is necessary to prevent thrombotic complications in patients undergoing percutaneous coronary intervention (PCI). Clopidogrel irreversibly blocks the P2Y12 receptor, therefore inhibiting platelet activation and aggregation. Aspirin inhibits platelets differently than clopidogrel, having an additive effect to clopidogrel in preventing platelet aggregation. However, despite receiving antiplatelet therapy with aspirin and/or clopidogrel, some patients still have complications after a PCI.1
The term clopidogrel resistance has been used to describe a failure to prevent thrombotic cardiovascular (CV) events and/or the failure of Clopidogrel in achieving its pharmacologic effects. Since ischemic CV disease is complex and involves much more than just thrombosis, no single agent can be expected to prevent all events. Importantly, a patient may have an ischemic CV event despite having the intended pharmacologic response to Clopidogrel. These patients have a treatment failure while resistance should be used in patients who do not achieve a pharmacologic response.1,2 The prevalence of clopidogrel resistance is reported to be 5%-44%. The wide range is thought to be due to dosing and possibly lack of a clear definition.1 Currently, treatment guidelines do not provide explicit recommendations on how to manage patients suspected of having clopidogrel resistance.3
Few studies have evaluated whether a higher maintenance dose of clopidogrel would improve platelet inhibition more than the standard dose. Von Beckerath and colleagues studied platelet inhibition in patients that received either 75 mg daily (n=29) or 150 mg daily (n=31) of clopidogrel for 30 days after receiving 600 mg loading dose before a PCI. This study showed more platelet inhibition in patients assigned to the 150 mg dose of clopidogrel than the 75 mg dose. These patients were not defined as having clopidogrel resistance.4
Patients with diabetes mellitus have an increased risk of ischemic CV events compared to patients without diabetes. It is thought that this increase in risk is due to platelet hyperreactivity. Data from the OPTIMUS study (Optimizing Antiplatelet Therapy in Diabetes Mellitus) indicated that patients with Type 2 diabetes (T2DM) and coronary artery disease who received 150 mg daily of clopidogrel instead of the standard dose of 75 mg daily had enhanced antiplatelet effects.5 However, about 60% of the patients receiving the high dose clopidogrel maintenance treatment still had suboptimal clopidogrel response via in vitro platelet aggregation studies.
Ari and colleagues evaluated the effects of high dose clopidogrel maintenance treatment on major adverse cardiovascular and cerebrovascular events (MACCE) in clopidogrel resistant patients who underwent elective PCI (all received a bare metal stent).6 It was a prospective, randomized, active control, two centered study. Patients were enrolled if they had been taking aspirin 100 mg/day for at least 5 days prior to the PCI and clopidogrel 75 mg/day for at least 3 days before the PCI. Patients were then divided into three groups: group 1, patients with platelet inhibition ≥ 40% as measured by the VerifyNow platelet analyzer, and groups 2 and 3 who had < 40% platelet inhibition. Group 1 received ASA 100 mg daily; group 2 patients received ASA 100 mg daily + Clopidogrel 75 mg daily, and group 3 who received ASA 100 mg daily + Clopidogrel 150 mg daily. Clopidogrel was stopped after one month in groups 2 and 3 while aspirin 100 mg/day was continued in all groups for 6 months. Follow up occurred after 1 and 6 months.